Use of Heterologous Vesiculovirus G Proteins Circumvents the Humoral Anti-envelope Immunity in Lentivector-Based In Vivo Gene Delivery

Abstract

Vesicular stomatitis virus Indiana strain glycoprotein (VSVind.G) mediates broad tissue tropism and efficient cellular uptake. Lentiviral vectors (LVs) are particularly promising, as they can efficiently transduce non-dividing cells and facilitate stable genomic transgene integration; therefore, LVs have an enormous untapped potential for gene therapy applications, but the development of humoral and cell-mediated anti-vector responses may restrict their efficacy. We hypothesized that G proteins from different members of the vesiculovirus genus might allow the generation of a panel of serotypically distinct LV pseudotypes with potential for repeated in vivo administration. We found that mice hyperimmunized with VSVind.G were not transduced to any significant degree following intravenous injection of LVs with VSVind.G envelopes, consistent with the thesis that multiple LV administrations would likely be blunted by an adaptive immune response. Excitingly, bioluminescence imaging studies demonstrated that the VSVind-neutralizing response could be evaded by LV pseudotyped with Piry and, to a lesser extent, Cocal virus glycoproteins. Heterologous dosing regimens using viral vectors and oncolytic viruses with Piry and Cocal envelopes could represent a novel strategy to achieve repeated vector-based interventions, unfettered by pre-existing anti-envelope antibodies.

Lentiviral Vector Bioprocessing

“…VSV-G LVs are typically applied in ex vivo therapies due to their inactivation by complement in human serum [ 71 ]. Additional immune responses against VSV-G are apparent in vivo [ 72 ] which can inhibit subsequent LV administration by adaptive immune responses [ 73 ]. Moreover, despite the ubiquity of LDL-R, clinically valuable resting lymphocytes for CAR-T therapies have particularly low expression of the receptor, and thus transduction is inefficient unless activated prior [ 74 ].…”

A tool with many applications: vesicular stomatitis virus in research and medicine

“…However, the use of LDLR and its family members is not universal to all vesiculoviruses. While the close phylogenetic relatives to VSV, Cocal, and Maraba viruses also interact with LDLR, it has been shown that Piry and Chandipura viruses do not [31,43]. This is thought to be due to the key residues on the glycoprotein which dictate the interaction with CR2 and CR3 domains not being conserved on all vesiculoviruses.…”

Lentiviral Vector Pseudotypes: Precious Tools to Improve Gene Modification of Hematopoietic Cells for Research and Gene Therapy

“…However, it is distinct from it in the sense that it is more resistant to complement-mediated inactivation by mouse and human sera, and it also confers an even wider tropism. Furthermore, CV glycoprotein pseudotyped LVs can be produced at higher titers and can transduce not only human cells, but also nonhuman primate and canine stem cells [32,33,65].…”